Low Rate of Bleeding with Factor IX Fusion Protein

Patients with severe hemophilia B had a low incidence of bleeding when treated in different therapeutic settings with long-acting recombinant factor IX fusion protein (eftrenonacog alfa), investigators in a multicenter trial reported.

Median annualized bleeding rates ranged from 1.4 to 17.7 for patients who received long-acting recombinant factor IX fusion protein (rFIXFc) for prophylaxis, treatment, or in the perioperative setting. Regardless of treatment indication, 90% of bleeding episodes resolved after a single injection.

"This study showed that rFIXFc is safe and effective for the treatment and prevention of bleeding events including those incurred during major surgeries, in previously treated adolescents and adults with hemophilia B," the authors concluded. "Fc fusion did not impair factor IX activity or result in increased immunogenicity. The prolonged half-life of rFIXFc allowed for effective prophylaxis, with injections every 1 to 2 weeks."

Prophylactic use of factor I improves outcomes in patients with hemophilia B, but the therapy's relatively short half-life necessitates frequent injections to maintain protective levels of the blood factor. Frequency of injection is often cited by patients as a factor in rejecting prophylactic treatment, the authors noted.

Use of bioengineered coagulation factors is one of several strategies under investigation as a means to reduce the injection burden for patients with hemophilia B. Additionally, investigation of gene-transfer therapy follows a pathway toward a potential cure for the disease.

To achieve a prolonged half-life, development of rFIXFc led to the combination of a single molecule of recombinant factor IX, covalently fused to the Fc domain of immunoglobulin G (IgG). With the attachment of Fc fusion proteins, neonatal Fc receptor and the endogenous IgG recycling pathway delay lysosomal degradation of IgG and the fusion proteins and recycle them back into circulation, according to the authors.

The evaluation of rFIXFc involved patients, ages 12 or older, with severe hemophilia B, defined as ≤2 IU of endogenous factor IX per deciliter. Patients also could qualify for the study if they were receiving prophylactic factor IX or had a history of eight or more bleeding episodes in the past year, and had received at least 100 injections of replacement factor IX.

Patients were assigned to four treatment groups according to the clinical site's standard of care: weekly prophylaxis followed by dose adjustment as needed; interval-adjusted prophylaxis followed by interval-adjusted continuation as needed; on-demand treatment for bleeding episodes; and treatment associated with perioperative care.

The trial included 123 male patients enrolled at 50 sites in 17 countries. Of those, 115 completed the study. Median duration of treatment was 51.6 weeks with weekly prophylaxis, 58.3 weeks for interval-adjusted prophylaxis, and 40.9 weeks for on-demand treatment. Median number of exposure days for those three groups were 55, 38, and 16 days, respectively.

The median rFIXFc dose in the weekly prophylaxis group was 45 IU/kg. In the interval-adjusted prophylaxis group, the median dosing interval was 12.5 days. Among patients who remained in the interval-adjusted dosing group for at least 6 months, 14 participants (53.8%) had a dosing interval of 14 days or longer during the last 3 months of the study.

"The reduction in the annualized bleeding rate with prophylaxis as compared with episodic treatment was consistent across all demographic and disease-based subgroups in prespecified subgroup analyses," the authors reported.

During the study, 636 bleeding episodes occurred, mostly spontaneous joint bleeding. One injection led to resolution of bleeding in 90.4% of episodes, and 97.3% resolved after two injections of rFIXFc.

For the 14 patients who underwent surgery, their surgeons rated hemostasis as excellent in all but one case, which was rated as good.

Among patients assigned to the prophylaxis groups, the annualized bleeding rate declined from 23.0 in the 12 months before enrollment to 2.5 during the study. The rate in the interval-adjusted group declined from 25.0 to 1.9. The rate did not decline in the group that continued episodic treatment (17.7 versus 18.0 before enrollment).

The most common adverse events in all but the perioperative group were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, headache, and hypertension. Additionally, 13 serious adverse events occurred, one of which was considered possibly related to study treatment.

The authors cautioned that the study was not designed to compare the two regimens, explaining that both the weekly dosing and interval-adjusted dosing regimens led to significantly reduced, annualized rates of bleeding versus episodic treatment. As a result, whether one approach was better than the other could not be determined, they added.

"In clinical practice, the two approaches may offer patients the choice between more frequent dosing which would maintain higher trough levels of factor IX, providing greater protection, and less frequent dosing, which would result in lower trough levels but would reduce the required frequency of injections," they wrote.

The study was supported by Biogen Idec, and Biogen Idec employees participated as investigators in the trial and as co-authors of the article.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.